The main objective of the proposal is to design, synthesize and investigate chemical delivery systems (CDS's) based on the concept of molecular packaging that make possible the brain delivery and brain targeting of the neuropeptide TRH or its analogues for potential treatment of the cognitive decline, associated with Alzheimer's disease. Neuropeptides cannot reach the brain after systemic administration, as the blood-brain-barrier (BBB) prevents entry of these hydrophilic compounds. In addition to physicochemical features (most peptides are hydrophilic), a highly active enzymatic barrier for peptides exists in the BBB which results in their rapid cleavage-fragmentation of peptides, even if they possess sufficient lipophilicity. The novel concept is to provide the peptide molecule a special the entire (intact) peptide segment into the brain, In the most important step, an enzymatic reaction locks-in the brain delivered molecule. A series of enzymatic biotransformations then cleave the protective functions and allow the formation of the biologically active species. Important structural element are the bulky polycyclic substituents (non-toxic steroid derivatives such as cholesteryl, cortienyl, or other lipophilic alkyl group, e.g., adamantanethyl) susceptible to cleavage from the peptide by esterase and/or lipase enzymes. Secondly, a dihydropyridine - pyridinium salt-type dual targetor allows the compound to remain at a sustained (locked-in) level after brain delivery. An additional element which may also be needed is a "spacer," consisting of one or two amino acid residues, or a carbamate function which is placed between the targetor and the neuropeptide to be delivered. The spacer allows enzymatic cleavage (endopeptidase or esterase) at the desired site resulting in the controlled and sustained release of the biologically active peptide. Preliminary results fully support the feasibility of the proposed approach. Design and synthesis, in vitro hydrolytic, oxidation, and peptide cleavage pattern studies will be carried out to evaluate the compounds, and select candidates for in vivo distribution experiments. Brain uptake and biotransformation of CDS's will be investigated by specific analytical techniques (high-performance liquid chromatography, mass spectrometry, and combinations thereof, already used successfully). Pharmacological tests will be performed to assess the hormonal and CNS effects induced by the central delivery of TRH including secretion of TSH, cholinergic neuron cytoprotection, and memory in tests of the memory deficits associated with aged and transection of the septal-hippocampal pathway.